Multi-omics reveals the lipid inventory of synaptic junctions and altered lipid signaling in environmental enrichment

Membrane lipids are essential components of synaptic junctions that have key functions in neurotransmission. In the first part of the study, we provide a quantitative lipid inventory of mouse and rat synaptic junctions. We next used a simultaneous multi-omics extraction and analysis workflow termed SIMPLEX to probe the interplay of proteins and lipids in synaptic signal transduction. We found that SIMPLEX is suitable to generate hypotheses about novel mechanisms underlying complex changes in synaptic connectivity elicited by environmental stimuli. As a proof of principle, this approach revealed that in mice exposed to an enriched environment reduced endocannabinoid signaling is linked to increased surface expression of AMPAR in a subset of Cannabinoid-receptor 1 positive synapses, a mechanism which likely regulates synaptic strength in an input-specific manner.